Response to immunotherapy is the main challenge of head and neck squamous cancer (HNSCC) treatment. Previous studies have indicated that tumor mutational burden (TMB) is associated with prognosis, but it is not always a precise index. Hence, investigating specific genetic mutations and tumor microenvironment (TME) changes in TMB-high patients is essential for precision therapy of HNSCC. A total of 33 HNSCC patients were enrolled in this study. We calculated the TMB score based on next-generation sequencing (NGS) sequencing and grouped these patients based on TMB score. Then, we examined the immune microenvironment of HNSCC using assessments of the bulk transcriptome and the single-cell RNA sequence (scRNA-seq) focusing on the molecular nature of TMB and mutations in HNSCC from our cohort. The association of the mutation pattern and TMB was analyzed in The Cancer Genome Atlas (TCGA) and validated by our cohort. 33 HNSCC patients were divided into three groups (TMB-low, -medium, and -high) based on TMB score. In the result of 520-gene panel sequencing data, we found that FAT1 and LRP1B mutations were highly prevalent in TMB-high patients. FAT1 mutations are associated with resistance to immunotherapy in HNSCC patients. This involves many metabolism-related pathways like RERE, AIRE, HOMER1, etc. In the scRNA-seq data, regulatory T cells (Tregs), monocytes, and DCs were found mainly enriched in TMB-high samples. Our analysis unraveled the FAT1 gene as an assistant predictor when we use TMB as a biomarker of drug resistance in HNSCC. Tregs, monocytes, and dendritic cells (DCs) were found mainly enriched in TMB-high samples.

中文翻译：

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FAT1作为肿瘤突变负荷特异性基因影响头颈鳞状细胞癌的免疫治疗效果


对免疫疗法的反应是头颈鳞状癌（HNSCC）治疗的主要挑战。先前的研究表明肿瘤突变负荷（TMB）与预后相关，但它并不总是一个精确的指标。因此，研究 TMB 高患者的特定基因突变和肿瘤微环境 (TME) 变化对于 HNSCC 的精准治疗至关重要。共有 33 名 HNSCC 患者参加了这项研究。我们根据下一代测序（NGS）测序计算了 TMB 评分，并根据 TMB 评分对这些患者进行分组。然后，我们通过评估大量转录组和单细胞 RNA 序列 (scRNA-seq) 来检查 HNSCC 的免疫微环境，重点关注我们队列中 TMB 的分子性质和 HNSCC 的突变。突变模式与 TMB 的关联在癌症基因组图谱 (TCGA) 中进行了分析，并由我们的队列进行了验证。根据 TMB 评分将 33 名 HNSCC 患者分为三组（TMB-低、-中和-高）。在520个基因组测序数据的结果中，我们发现FAT1和LRP1B突变在TMB高的患者中非常普遍。 FAT1 突变与 HNSCC 患者对免疫治疗的耐药性相关。这涉及到许多代谢相关的通路，如 RERE、AIRE、HOMER1 等。在 scRNA-seq 数据中，发现调节性 T 细胞（Treg）、单核细胞和 DC 主要富集在 TMB 高的样本中。当我们使用 TMB 作为 HNSCC 耐药性的生物标志物时，我们的分析揭示了 FAT1 基因作为辅助预测因子。研究发现，Treg、单核细胞和树突状细胞 (DC) 主要富集在 TMB 高的样本中。